Apelin APJ triggers a variety of cellular signaling pathways

Apelin/APJ triggers a variety of cellular signaling pathways (Fig. 1). Recent studies from our laboratory showed that apelin-13 induces vascular smooth muscle cell (VSMC) proliferation by the upregulation of Cyclin D1 expression, which is involved in an ERK-dependent activation of Jagged-1/Notch3 signaling [15]. Lu and colleagues reported that apelin/APJ increases the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) in human umbilical vein endothelial Lurasidone HCl by promoting nuclear translocation of nuclear factor kappa-κB (NF-κB) and then increasing phosphorylation of c-Jun N-terminal kinase (JNK) via a pertussis toxin (PTX)-sensitive G-Protein [16]. In contrast with this report, apelin inhibits MCP-1 expression in endothelial cells through activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, followed by suppression of Smad3 [17]. This discrepancy may be due to different experimental protocols and apelin isoforms. It has been suggested that apelin ameliorates TNF-α-induced reduction of glycogen synthesis in HepG2 cells by improving the JNK/insulin receptor substrate 1 (IRS1)/glycogen synthase kinase (GSK) signaling pathway, indicating the anti-insulin resistance properties of apelin [18]. Knockdown of apelin expression in primary amnion cells using siRNA significantly increases IL-1β-induced IL-6 and IL-8 secretion as well as cyclooxygenase-2 (COX-2)-mediated prostaglandin E2 (PGE2) release [14]. Apelin/APJ system inhibits histone deacetylase (HDAC) 4 and HDAC5 phosphorylation and subsequently upregulates myocyte enhancer factor 2 (MEF2) expression, leading to Kruppel-like factor 2 (KLF2) transcription in endothelial cells [19]. Than et al. have demonstrated that apelin interaction with APJ receptor suppresses lipolysis in mature adipocytes, and the mechanisms are associated with AMP kinase (AMPK) dependent enhancement of perilipin expression [20]. Activation of APJ has been shown to stimulate angiopoietin-1 (Ang-1) expression, which in turn triggers the synthesis of vascular endothelial growth factor type A (VEGFA) and platelet-derived growth factor-BB (PDGF-BB) in HepG2 cells [10]. In addition, treatment with apelin can significantly promote Fas-induced hepatocyte apoptosis at least partially via JNK activation [21]. However, Cui and colleagues found that apelin markedly inhibits serum deprivation-induced apoptosis of human VSMCs, and the anti-apoptotic action is mediated through stimulating PI3K/Akt signaling dependent increase of Bcl-2 protein expression and decrease of Bax protein expression [22]. Many more apelin/APJ-regulated cellular signaling pathways will be probably discovered in future studies.
Cardiovascular physiological actions of apelin and APJ Apelin/APJ system has a number of physiological actions such as fluid homoeostasis, glucose homeostasis, feeding behavior and immunity [23]. Several lines of evidence demonstrate that the cardiovascular system is the main target of apelin and its receptor APJ (Fig. 2). Apelin has been reported to lower arterial blood pressure through a nitric oxide (NO)-dependent mechanism [24], which is abrogated in APJ-deficient mice [25]. In addition, administration of apelin causes a concentration-dependent vasodilatation in endothelium-intact mammary artery but has no effect after endothelial removal, suggesting an endothelium-dependent hypotensive effect of apelin [26]. Injection of apelin into the ischemic myocardium facilitates neovascularization in the peri-infarct area through paracrine activity [27]. Treatment with apelin also decreases systemic venous tone [28], and inhibits arginine vasopressin release to promote diuresis [29]. On the other hand, intraperitoneal injection of apelin reduces left ventricular preload and afterload without causing cardiac hypertrophy [30]. In a study of isolated perfused rat hearts, apelin is identified as one of the most potent endogenous positive inotropic substances [31]. Moreover, isolated left ventricular cardiomyocytes lacking either apelin or APJ display less sarcomeric shortening and impaired velocity of contraction and relaxation with no difference in calcium transient [32]. These findings indicate an important role for apelin/APJ system in maintaining basal cardiac function.